9-134885816-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004108.3(FCN2):c.478G>A(p.Ala160Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FCN2 NM_004108.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.399

Genes affected

FCN2 (HGNC:3624): (ficolin 2) The product of this gene belongs to the ficolin family of proteins. This family is characterized by the presence of a leader peptide, a short N-terminal segment, followed by a collagen-like region, and a C-terminal fibrinogen-like domain. This gene is predominantly expressed in the liver, and has been shown to have carbohydrate binding and opsonic activities. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06471756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FCN2	NM_004108.3	c.478G>A	p.Ala160Thr	missense_variant	6/8	ENST00000291744.11
FCN2	NM_015837.3	c.364G>A	p.Ala122Thr	missense_variant	5/7
FCN2	XM_011518392.4	c.445G>A	p.Ala149Thr	missense_variant	6/8
FCN2	XM_006717015.5	c.331G>A	p.Ala111Thr	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FCN2	ENST00000291744.11	c.478G>A	p.Ala160Thr	missense_variant	6/8	1	NM_004108.3	P1
FCN2	ENST00000350339.3	c.364G>A	p.Ala122Thr	missense_variant	5/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.478G>A (p.A160T) alteration is located in exon 6 (coding exon 6) of the FCN2 gene. This alteration results from a G to A substitution at nucleotide position 478, causing the alanine (A) at amino acid position 160 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	11
Dann	Benign	0.95
DEOGEN2	Benign	0.0040	T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.50	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.069
Sift	Benign	0.58	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.020	B;B
Vest4		0.15
MutPred		0.36		Loss of catalytic residue at A160 (P = 0.0345);.;
MVP		0.59
MPC		0.074
ClinPred		0.081	T
GERP RS		-0.28
Varity_R		0.14
gMVP		0.086

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-137777662;